32.1 Structure and Physiology of the immune system Flashcards
What are the primary lymphoid organs?
The site of lymphocyte production, not activation.
What is the PLO for T-cells?
Bone marrow, then thymus.
What is the PLO for B-cells?
Bone marrow
Describe the structure of the thymus
Made up of several lobules
Each lobule is split into two regions = dense cortical (outer) and less dense medullary (central) regions
Wrapped in a capsule
What is the function of the epithelial cells in the cortex of the thymus?
Releases signals to thymic progenitor cells which activates the Notch1 receptor to instruct the precursor to become committed to a T cell lineage rather than B cell
Which cell expresses the MHC molecules during positive selection?
cTEC (cortical thymic epithelial cells)
Which cell types are found in the cortex of the thymus?
Immature thymocytes closely associated to branched cortical epithelial cells (thymic stroma analogous to stromal cells in bone marrow) and macrophages which kill apoptotic thymocytes
Which cell types are found in the medulla of the thymus?
Mature thymocytes and medullar epithelial cells
Macrophages
Dendritic cells
Hassans corpsucles - cell degradation
What is the positive selection of T cells in the PLO?
The rescue of double positive thymocytes from programmed cell death and their maturation into CD4 or CD8 single positive cells based on the avidity of the beta chain.
Describe the process of thymocyte (T cell progenitor) differentiation.
- T cells progenitors in the outer thymus begin as double-negative T cells that express neither CD4 or CD8
- During this time, VDJ recombination occurs
- First the beta chain is rearranged (using VDJ recombinase).
- While the beta chain is being rearranged, it is complexed with an invariant pT-alpha chain. Ligation of the pre-TCR terminates beta rearrangement and alpha rearrangement can occur. This occurs when the the pre-TCR undergoes auto-dimerisation (it is its own ligand), signalling that it is somewhat functional.
- Then the alpha chain is rearranged (since the beta chain locus is inaccessible and the alpha chain locus is accessible to the VDJ recombinase).
- This induces the T cell to then become double positive, expressing both CD4 and CD8
- The T cell proliferates ready for positive selection
- Positive selection leads to only either CD4 or only CD8 being expressed
What is the difference in the T cells found in the cortex and the medulla of the thymus?
Cortical T cells = proliferating immature cells that are becoming committed to a T cell lineage
Medullary T cells = immature T cells undergoing thymic selection
What are the three types of cell that are important in T cell development and central tolerance?
- Cortical thymic epithelial cells (cTECs) -> Positive selection
- Medullary thymic epithelial cells (mTECs) + Dendritic cells -> Negative selection
This means that cells travelling from the outer cortex to inner medulla first undergo postive selection and then negative selection.
In what order do positive and negative selection of lymphocytes occur?
Positive then negative
How does positive selection of T cells occur?
- Cortical thymic epithelial cells (cTECs) have a stellate morphology and form a 3-dimensional network with no basement membrane
- This means there is interaction between developing T cells and the epithelial cells
- The cTECs constitutively express both MHC class I and class II
- If the TCR binds more to the MHC class I than class II, then the CD8 receptor is stabilised and the CD4 receptor is lost
- If the TCR binds more to the MHC class II than class I, then the CD4 receptor is stabilised and the CD8 receptor is lost
- If there is insufficient affinity, then the cell dies by apoptosis
What are the consequences of positive selection of T cells?
- Rescues the T cells from apoptosis
- Imposes MHC-restricted antigen recognition on the emerging T cell repertoire
- Lineage commitment to either the CD4+ helper T cell lineage or to the lineage of CD8+ CTL
How is positive and negative selection distinguished if both processes involve binding self peptides: self MHC?
Depends on the threshold of avidity (affinity hypothesis)
Low affinity interactions rescues the cells from death = positive selection
High affinity interactions induces apoptosis = negative selection
What is the purpose of negative selection of T cells?
It prevents self-reactive T cells from surviving and leaving the thymus.
How are T cells prevented from leaving the thymus before negative selection occurs?
- Capillaries draining the cortex are impermeable to plasma proteins or the passage of cells
- Vessels in the cortex are composed of non-fenestrated endothelium and a thick basal lamina
- A reticular sheath surrounds the vessels composed of reticular cells and macrophages
Where does negative selection occur?
In the medulla (part in the cortex by cTEC) mediated by medullary epithelial cells (mTEC) and dendritic cells
What are the major surface molecules of T cells?
T cell Ag receptor, CD3, CD4, CD8, adhesion molecules, CK + Chemokine receptors (e.g. IL-2R).
What are the major surface molecules of B-cells?
Surface Ig, MHC class II, adhesion molecules, Chemokine and CK receptors.
What are the individual co-stimulatory molecules?
CD40L, CD28, and other signalling molecules (e.g. PD1, CTLA4, Fas ligand and Fas (CD95))
List the major surface molecules on B cells and what they bind to (6 types)
BCR (antibody bound) binds to antigen
CD20 (defines B cell)
CD40 - costimuatory molecule that binds to CD40L on T helper cells to become activated
Chemokine receptors
Toll like receptors (TLRs)
CD80 - binds to CD28 on T cells to activate them
List the negative regulators of T cell activation. What do they bind to?
EXPRESSED BY T CELLS:
PD-1 (programmed death-1)
CTLA4 (CD152) : Binds to same costimulatory ligands as CD28 (CD80 and CD86) to inhibit T cell activation
What are the major surface molecules on T cells and what do they bind to? (6 types)
TCR - binds to antigen:MHC complex
CD4 or CD8 - stabilises MHC/peptide:TCR complex
CD3 - T cell co receptor that mediates signal transduction
CD28 - ESSENTIAL co stimulatory molecule needed for T cell activaton, binds to CD80 (aka B7) on antigen presenting cells
Adhesion molecules (L-selectin,
Chemokine receptors (IL-2R) - binds to cytokines needed for activation
What is expressed on T helper cells that is not expressed on T effector cells?
CD40L on follicular T helper cells
What is the role of Fas (CD95) and Fas ligand? Which cells express it?
Effector T cells express Fas which binds to Fas ligand (CD178) to induce apoptosis once an infection has been cleared
Which chemokines attract B cells to follicles?
CXCL13
Which chemokines attract T cells to follicles?
CCL21 and CCL19
Which family of ligands does CD28 bind to?
B7 family
What are some other signalling molecules on lymphocytes that you need to know?
- PD1 -> Suppresses T cell inflammatory activity by promoting apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes and it reduces apoptosis in regulatory T cells.
- CTLA-4 -> Suppresses T cell inflammatory activity. When CTLA-4 is bound to another protein called B7, it helps keep T cells from killing other cells, including cancer cells.
- Fas and Fas ligand -> Involved in apoptosis
How does the location of the secondary lymphoid organs contribute to their function?
They are the origin of the immune responses. Hence their location is sited to monitor pathogen entry.
What are the secondary lymphoid organs?
Lymph nodes, Spleen, Peyer’s patches.
What do the lymph nodes monitor?
Solid tissues
What does the spleen monitor?
Blood
What do Peyer’s patches and equivalent (MALT/ GALT) monitor?
mucosae
Describe the path taken by circulating lymphocytes
Lymph node
Efferent lymphatic vessel
Venous circulation
Arterial circulation (spleen)
High endothelial venules
Lymph node
Describe the structure of secondary lymphoid organs
Outer capsule surrounding them
Follicles interspersed in the organ adjacent to T cell zones
Lymph received through afferent lymphatic vessels which drain all tissues accumulates in the subcapsular sinus and seeps into deep structures
Paracortex contains high endothelial venules
Arteries and veins also supply lymph nodes
Describe the structure of the spleen. How is this different to lymph nodes?
Contains red pullp and white pulp
White pulp contains B cell follicles and T cell zones
NOT SUPPLIED BY AFFERENT LYMPHATIC VESSELS
Recieve input via splenic artery and this is distributed to the arterioles
What are High endothelial venules?
Site of lymphocyte exit from blood.
Describe the concept of primary follicles, secondary follicles and germinal centres.
These are all structures within secondary lymphoid organs (lymph nodes and spleen):
- Primary follicles contain naive B lymphocytes
- Secondary follicles are those that have developed a germinal centre
- Germinal centres are the sites of actived B cell proliferation and somatic hypermutation
In other words, B cells in primary follicles are activated during the immune response and then form germinal centres. The follicles are then known as secondary follicles.
What body compartments do each of the secondary lymphoid organs sample?
- Spleen is highly vascularised, so it samples the blood
- Peyer’s patches sample the gut
- Lymph nodes drain tissue fluid from interstitial tissues
Describe the structure and function of the spleen.
It is made of two parts:
- Red pulp -> Contains a store of erythrocytes in case of haemorrhage, No immunological function
- White pulp -> Wraps around arterioles (periarterial lymphatic sheath) and contains:
- Naive T cells freely arranged
- Primary follicles containing naive B cells
Describe the structure and function of lymph nodes.
- Afferent lymphatics bring tissue fluid in
- Tissue fluid accumulates in the marginal sinus (just inside the capsule), then percolates into the medulla, from which it exits via the efferent lymphatic
- Cords in the medulla are made up of plasma cells that can secrete IgM antibodies (they are the source of the IgM that is produced early in the primary immune response)
- The IgM exits at the efferent lymphatic and enters the blood at the subclavian vein
- The paracortex contains naive T cells
- The primary follicles contain naive B cells
What is the structure of Peyer’s patches?
small clusters of lymphatic tissue within the lamina propria of the small intestine extending to the submucosa of the ileum.
*They are NOT surrounded by a connective tissue capsule.
